Ruthenium(II) catalysts for use in stereoselective cyclopropanations

ABSTRACT

Chiral ruthenium catalysts comprising salen and alkenyl ligands are provided for stereoselective cyclopropanation, and methods of cyclopropanation are provided. The chiral ruthenium catalyst is prepared in situ by combining an alkenyl ligand, a deprotonated chiral salen ligand, and a ruthenium (II) metal. A preferred catalyst is prepared in situ by combining 2,3-dihydro-4-venylbenzofuran, deprotonated 1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butyl-salicylidene) and RuCl 2 (p-cymene)] 2 .

TECHNICAL FIELD

Chiral catalysts for cyclopropanation, methods of preparation andmethods of forming chiral cyclopropyl products are provided herein.

BACKGROUND

The biological activities of many pharmaceuticals, fragrances, foodadditives and agrochemicals are often associated with their absolutemolecular configuration. While one enantiomer gives a desired biologicalfunction through interactions with natural binding sites, anotherenantiomer usually does not have the same function and sometimes hasdeleterious side effects. As such, chemical synthesis of biologicallyactive compounds are usually directed at the desired enantiomericallypure form.

Cyclopropanes are particularly challenging to synthesizeenantiomerically pure. Especially for commercial applications,stereoselective cyclopropanations must give good diastereo- andenantioselectivity in high yield and purity at a reasonable cost. Oneapproach that is particularly efficient, is stereoselective catalysisbecause a small amount of a chiral catalyst can be used to produce alarge quantity of the desired chiral cyclopropyl compound. Transitionmetal catalysts are typically employed to catalyze the reaction betweena diazoester and an olefin substrate to form a chiral cyclopropylproduct.

Current stereoselective cyclopropanation methods using transition metalcatalysis, are nonoptimal for commercialization due to the use of alarge excess olefin substrate or diazoester in order to drive thereaction to completion. Miller et al. (Angew. Chem nt. Ed. 2002, 41,2953-2956) report an isolated ruthenium catalyst formed from a chiralsalen ligand and pyridine or phosphine ligands. The stereoselectivecyclopropanation method of Miller et al. employs an isolated chiralruthenium catalyst and five equivalents of the olefin substrate relativeto the amount of diazoester employed. In commercial applications, theolefin substrates are often complex and require multi-step syntheses. Asa result, using an excess of the olefin substrate not only wastesmaterial, but also increases cost and lowers the throughput of thechemical process. On the other hand, using a large excess of thediazoester to drive the reaction to completion is undesirable due tosafety concerns on large scale. Furthermore, use of excess reagents canlead to increased impurities and purification difficulties. Finally, theuse of an isolated chiral catalyst can be undesirable in commercialapplications because of the increased number of steps in a chemicalprocess, increasing cycle time, as well as safety issues associated withhandling transition metal catalysts. What is needed, are efficienttransition metal catalyzed stereoselective cyclopropanation methodsemploying mild and safe conditions.

SUMMARY OF THE INVENTION

In one embodiment, a method of stereoselective cyclopropanation isprovided. The stereoselective cyclopropanation reaction comprisescombining a carbene precursor and an alkenyl substrate in the presenceof a chiral catalyst to form a cyclopropyl product. The chiral catalystis formed in situ by combining an alkenyl ligand with a deprotonatedchiral ligand and a ruthenium (II) metal.

In another embodiment, a catalyst for stereoselective reactions isprovided. The catalyst is prepared in situ by combining an alkenylligand and a deprotonated chiral ligand in the presence of a ruthenium(II) metal. The alkenyl ligand is of formula (I):

and the deprotonated ligand is of formula (III):

where R¹, R², R³, R⁴, R⁵, R⁶, M¹ and M² are defined below.

Thus, there is disclosed a method of stereoselective cyclopropanationcomprising the step of combining a carbene precursor and an alkenylsubstrate in the presence of a chiral catalyst to form a cyclopropylproduct, the chiral catalyst is prepared in situ by the step ofcombining an alkenyl ligand and a deprotonated chiral ligand in thepresence of a ruthenium (II) metal; wherein the alkenyl ligand is offormula (I):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ isselected from the group consisting of hydrogen, and C₁₋₈ alkyl; andwhere R⁵ and R⁶ together with the atoms to which they are attached mayform a carbocyclic ring; wherein the deprotonated chiral ligand is offormula (III):

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀ heteroaryl; whereR³ and R⁴ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted C₅₋₁₀ heteroaryl and substituted orunsubstituted arylalkyl; where R³ and R⁴ together with the atoms towhich they are attached may form a ring; and where M¹ and M² are each acounterion independently selected from the group consisting of Group Imetal ions and Group II metal ions.

There is further disclosed a method of stereoselective cyclopropanationconsisting of the steps of combining an alkenyl ligand and adeprotonated chiral ligand in the presence of a ruthenium (II) metal toform a chiral catalyst in situ; wherein the alkenyl ligand is of formula(I):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ isselected from the group consisting of hydrogen, and C₁₋₈ alkyl; andwhere R⁵ and R⁶ together with the atoms to which they are attached mayform a carbocyclic ring; wherein the deprotonated chiral ligand is offormula (III):

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀ heteroaryl; whereR³ and R⁴ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted C₅₋₁₀ heteroaryl and substituted orunsubstituted arylalkyl; where R³ and R⁴ together with the atoms towhich they are attached may form a ring; and where M¹ and M² are each acounterion independently selected from the group consisting of Group Imetal ions and Group II metal ions; and combining a carbene precursorand an alkenyl substrate in the presence of the chiral catalyst to forma cyclopropyl product.

Also disclosed is the stereoselective cyclopropanation of a carbeneprecursor and an alkenyl substrate with a chiral catalyst of theformulae (V) or (VI):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ isselected from the group consisting of hydrogen, and C₁₋₈ alkyl; andwhere R⁵ and R⁶ together with the atoms to which they are attached mayform a carbocyclic ring; where R¹ and R² are each independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀heteroaryl; where R³ and R⁴ are each independently selected from thegroup consisting of substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino,substituted or unsubstituted C₃₋₁₀ heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted C₅₋₁₀ heteroaryland substituted or unsubstituted arylalkyl; where R³ and R⁴ togetherwith the atoms to which they are attached may form a ring; and where M¹and M² are each a counterion independently selected from the groupconsisting of Group I metal ions and Group II metal ions; theimprovement comprising generating the chiral catalyst in situ.

Further, there is disclosed a catalyst for stereoselective reactionsprepared by the step of combining an alkenyl ligand and a deprotonatedchiral ligand in the presence of a ruthenium (II) metal; wherein thealkenyl ligand is of formula (I):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ isselected from the group consisting of hydrogen, and C₁₋₈ alkyl; andwhere R⁵ and R⁶ together with the atoms to which they are attached mayform a carbocyclic ring; wherein the deprotonated chiral ligand is offormula (III):

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀ heteroaryl; whereR³ and R⁴ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted C₅₋₁₀ heteroaryl and substituted orunsubstituted arylalkyl; where R³ and R⁴ together with the atoms towhich they are attached may form a ring; and where M¹ and M² are each acounterion independently selected from the group consisting of Group Imetal ions and Group II metal ions.

DETAILED DESCRIPTION Definitions

“Alkyl” by itself or as part of another substituent refers to asaturated hydrocarbon group which may be linear, cyclic, or branched ora combination thereof having the number of carbon atoms designated(i.e., C₁₋₈ means one to eight carbon atoms). Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl,cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.Alkyl groups can be substituted or unsubstituted, unless otherwiseindicated. Examples of substituted alkyl include haloalkyl,perhaloalkyls, thioalkyl, aminoalkyl, and the like.

“Alkoxy” refers to —O-alkyl. Examples of an alkoxy group includemethoxy, ethoxy, n-propoxy etc.

“Alkylamino” refers to —NHR′ and —NR′R″ where R′ is alkyl and R″ ishydrogen or alkyl. Examples of alkylamino groups include methylamine,ethylamine, isopropylamine, butylamine, dimethyl amine, diisopropylamineand the like.

“Alkenyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkenyl groups with2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3carbon-carbon double bonds. Examples of alkenyl groups include ethenyl,n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl,cyclopentenyl and the like. Alkenyl groups can be substituted orunsubstituted, unless otherwise indicated.

“Aryl” refers to a polyunsaturated, aromatic hydrocarbon group having asingle ring (monocyclic) or multiple rings (bicyclic), which can befused together or linked covalently. Aryl groups with 6-10 carbon atomsare preferred, where this number of carbon atoms can be designated byC₆₋₁₀, for example. Examples of aryl groups include phenyl andnaphthalene-1-yl, naphthalene-2-yl, biphenyl and the like. Aryl groupscan be substituted or unsubstituted, unless otherwise indicated.

“Heterocyclyl” refers to a saturated or unsaturated non-aromatic ringcontaining at least one heteroatom (typically 1 to 5 heteroatoms)selected from nitrogen, oxygen, sulfur or silicon. The heterocyclyl ringmay be monocyclic or bicyclic. Preferably, these groups contain 0-5nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably,these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Examples of heterocycle groups include pyrrolidine, piperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidineand the like.

“Heteroaryl” refers to an aromatic group containing at least oneheteroatom, where the heteroaryl group may be monocyclic or bicyclic.Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, pyrrolyl, thiazolyl, furyl or thienyl.

Heterocyclyl and heteroaryl can be attached at any available ring carbonor heteroatom. Each heterocyclyl and heteroaryl may have one or morerings. When multiple rings are present, they can be fused together orlinked covalently. Each heterocyclyl and heteroaryl must contain atleast one heteroatom (typically 1 to 5 heteroatoms) selected fromnitrogen, oxygen or sulfur. Preferably, these groups contain 0-5nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably,these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Heterocyclyl and heteroaryl groups can be substituted orunsubstituted, unless otherwise indicated. For substituted groups, thesubstitution may be on a carbon or heteroatom.

Suitable substituents for substituted alkyl, substituted alkenyl, andsubstituted alkynyl include halogen, —CN, —CO₂R′, —C(O)R′, —C(O)NR′R″,oxo (═O or —O⁻), —OR′, —OC(O)R′, —OC(O)NR′R″—NO₂, —NR′C(O)R″,—NR′″C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR′S(O)R″, —NR′S(O)₂R′″,—NR′″S(O)NR′R″,—NR′″S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl. The numberof possible substituents range from zero to (2m′+1), where m′ is thetotal number of carbon atoms in such radical.

Suitable substituents for substituted aryl, substituted heteroaryl andsubstituted heterocyclyl include halogen, —CN, —CO₂R′, —C(O)R′,—C(O)NR′R″, oxo (═O or —O⁻), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO₂,—NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR′S(O)R″, —NR′S(O)₂R″,—NR′″S(O)NR′R″, —NR′″S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10 membered heterocyclyl. The numberof possible substituents range from zero to the total number of openvalences on the aromatic ring system.

As used above, R′, R″ and R′″ each independently refer to a variety ofgroups including hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedaryloxyalkyl. When R′ and R″ are attached to the same nitrogen atom,they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring (for example, —NR′R″ includes 1-pyrrolidinyl and4-morpholinyl). Furthermore, R′ and R″, R″ and R′″, or R′ and R′″ maytogether with the atom(s) to which they are attached, form a substitutedor unsubstituted 5- ,6- or 7-membered ring.

“Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S)and silicon (Si).

It will be apparent to one skilled in the art that certain compounds ofthe present invention may exist in tautomeric forms, all such tautomericforms of the compounds being within the scope of the invention. Certaincompounds of the present invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers (e.g., separate enantiomers)are all intended to be encompassed within the scope of the presentinvention. The compounds of the present invention may also containunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The term “asymmetric” refers to a molecule lacking all traditionalelements of symmetry.

The term “carbocyclic ring” refers to a 5-10 membered ring in which theall of the ring atoms are carbons. A carbocyclic ring may be aromatic ornonaromatic.

The term catalysis or “catalyzed” refers to a process in which arelatively small amount of a material increases the rate of a chemicalreaction and is not itself consumed in the reaction.

The term “catalytic amount” refers to a substoichiometric amount of thecatalyst relative to a reactant.

The term “chiral” refers to a molecule or conformation which is notsuperimposable with its mirror image partner.

“Chiral catalyst” refers to a molecule which is not superimposable withits mirror image partner and that increases the rate of a chemicalreaction without itself being consumed. In a stereoselective catalyticreaction, the chiral catalyst will serve to catalyze the reaction, whilealso providing enantioselectivity.

“Chiral ligand” refers to a molecule or ion that surrounds a metal,especially a transition metal, in a metal ion complex as a Lewis base,where the molecule in one which is not superimposable with its mirrorimage partner.

“Complex” refers to a coordination compound formed by the union of oneor more electronically rich molecules or atoms capable of independentexistence with one or more electronically poor molecules or atoms, whichis also capable of independent existence.

“Diastereomer” refers to one of a group of stereoisomers which is notrelated to another stereoisomer of the group as a mirror image.

“Diastereoselective” refers to a process which favors production of oneof the two possible diastereomers of a reaction product. For example, achemical reaction would be diastereoselective if it produces the twodiastereomers of a chiral product in unequal amounts. Such a reaction issaid to exhibit diastereoselectivity.

“Enantiomer” refers to one of a pair of molecular species that aremirror images of each other and not superimposable.

“Enantiomerically enriched” refers to a mixture of enantiomers, in whichone of the enantiomers is present in a greater amount than the partnerenantiomer. An “enantiomerically enriched” product will have anenantiomeric excess (“% ee”), of more than 0 but less than 100%.“Enantiomeric excess” (ee) is equal to 100 times the mole fraction ofthe major enantiomer minus the mole fraction of the minor enantiomer. Ina mixture of a pure enantiomer (R or S) and a racemate, ee is thepercent excess of the enantiomer over the racemate. Representative of anenantiomerically enriched sample is a mixture of 25% of one enantiomerand 75% of the partner enantiomer. The mole fractions of each enantiomerare 0.25 and 0.75 respectively. The enantiomeric excess is calculated as(0.75−0.25)×100=50. Thus, the enantiomerically enriched sample has an eeof 50%.

“Enantioselective” refers to a process which favors production of one ofthe two possible enantiomers of a reaction product. For example, achemical reaction would be enantioselective if it produces the twoenantiomers of a chiral product in unequal amounts. Such a reaction issaid to exhibit enantioselectivity.

“Ligand” refers to a molecule or ion that surrounds a metal, especiallya transition metal, in a complex and serves as a Lewis base (i.e. anelectron pair donor).

“Metal” refers to elements located in Groups 5 and 6 of the periodictable with atomic numbers of 23 to 74.

“Phosphorus donating ligand” refers to a ligand containing a phosphorusatom, where the phosphorus atom can act as the Lewis base and electronpair donor to form a complex with a metal. Examples includetriphenylphosphine, tributylphosphine and the like.

“Pyridyl donating ligand” refers to a pyridine compound which can act asa ligand, where the nitrogen atom of the pyridine ring can act as theLewis base and electron pair donor to form a complex with a metal. Apyridyl donor ligand can be substituted or unsubstituted.

“Stereoisomer” refers to isomers of identical constitution (i.e. bondconnectivity), but which differ in their arrangement in space.

“Stereoselective” refers to preferentially forming one stereoisomer overanother in a chemical reaction. If the stereoisomers are enantiomers,the chemical reaction is an enantioselective reaction. If thestereoisomers are diastereomers, the chemical reaction is adiastereoselective reaction.

“Tertiary amine ligand” refers to nitrogen atom which is substitutedwith three groups other than hydrogen. Suitable substituents includealkyl and aryl groups. The tertiary amine ligand contains a nitrogenatom that can act as a Lewis base and electron pair donor to form acomplex with a metal.

The term “carbene precursor” refers to a compound used to generate acarbene at the coordination site of a transition metal.

Chiral Catalyst

In a first aspect of the first embodiment, a chiral catalyst is formedby combining a deprotonated chiral ligand, an alkenyl ligand and aruthenium (II) metal. A ruthenium (II) metal is any ruthenium metal withan oxidation state of 2⁺. Examples of ruthenium (II) metals includeruthenium (II) chloride (RuCl₂); ruthenium (II) bromide (RuBr₂);ruthenium (II) iodide (RuI₂); tricarbonyldichlorodiruthenium (II) dimmer([RuCl₂(CO)₃]₂); K₄[Ru(CN)₆].3H₂O; bis(cyclopentadienyl)ruthenium (II)(Ru(C₅H₅)₂); bis(pentamethylcyclopentadienyl)ruthenium (II)(Ru(C₅Me₅)₂); dichloro(η⁴-cyloocta1,5-diene)ruthenium(II);dichloro(1,5-cyclooctadiene)ruthenium(II);tetrachlorobis(4-cymene)diruthenium(II), andtetrachlorobis(η⁶-p-cymene)diruthenium(II) ([RuCl₂(p-cymene)]₂).Preferably the ruthenium (II) metal is [RuCl₂(p-cymene)]₂.

Alkenyl Ligand

In one aspect of the first embodiment of the present invention analkenyl ligand is provided of the formula (I):

where R⁵ is selected from the group consisting of hydrogen, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted C₅₋₁₀ heteroaryl, and substituted orunsubstituted C₃₋₁₀ heterocycle; and

R⁶ is selected from the group consisting of hydrogen and substituted orunsubstituted C₁₋₈ alkyl; or

R⁵ and R⁶ together with the atoms to which they are attached may form acarbocyclic ring.

In one embodiment, the alkenyl ligand is of formula II:

which is also referred to as 2,3-dihydro-4-vinylbenzofuran.

In another embodiment, the alkenyl ligand is selected from the groupconsisting of ethylene, cyclohexene, 1-hexene and2,3-dihydro-4-vinylbenzofuran.

In one embodiment, R⁵ is selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, and substituted orunsubstituted C₃₋₁₀ heterocycle.

In one embodiment, R⁶ is hydrogen.

In one embodiment, R⁶ is hydrogen, and R⁵ is other than hydrogen.

In another embodiment, R⁶ is hydrogen, and R⁵ is substituted orunsubstituted C₃₋₁₀ heterocycle.

In another embodiment R⁶ is hydrogen, and R⁵ is substituted orunsubstituted C₁₋₈ alkyl.

In another embodiment, R⁶ and R⁵ are each independently substituted orunsubstituted C₁₋₈ alkyl.

Deprotonated Chiral Ligand

The deprotonated chiral ligand of the present invention is of theformula (III):

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₁₀ heterocyclyl, and substituted or unsubstituted C₅₋₁₀ heteroaryl;

R³ and R⁴ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted C₅-₁₀ heteroaryl, and substituted orunsubstituted arylalkyl; or R³ and R⁴ together with the atoms to whichthey are attached may form a ring;

M¹ and M² are each a counterion. Preferably, M¹ and M² are the same butthey may be different. More preferably, M¹ and M² are each independentlyselected from Group I or Group II metal ions. Group I metals are Li, Na,K, Rb, Cs and Fr. Group II metals are Be, Mg, Ca, Sr, Ba, and Ra. Evenmore preferably, M¹ and M² are selected from the group consisting ofLi⁺, Na⁺, MgCl⁺ and MgBr⁺. Most preferably, M¹ and M² are each Li⁺.

In one embodiment, the deprotonated chiral ligand is of the formula(IV):

also referred to as1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butyl-salicylidene).Preferably, the chiral ligand is the (1R,2R)-(−) enantiomer. In otherembodiments, the (1S,2S)-(+) enantiomer is preferred.

In one embodiment, R¹ and R² are each independently selected from thegroup consisting of substituted or unsubstituted C₁₋₈ alkyl, andsubstituted or unsubstituted C₆₋₁₀ aryl.

In another embodiment, R¹ and R² are each independently substituted orunsubstituted C₁₋₈ alkyl.

In another embodiment, R¹ and R² are each independently a perfluoro C₁₋₈alkyl.

In a highly preferred embodiment, R¹ and R² are each t-butyl.

In one embodiment, R³ and R⁴ are each independently selected from thegroup consisting of substituted or unsubstituted C₁₋₈ alkyl, andsubstituted or unsubstituted C₆₋₁₀ aryl.

In another embodiment, R³ and R⁴ are each independently a substituted orunsubstituted C₁₋₈ alkyl.

In a highly preferred embodiment, R³ and R⁴ together with the atoms towhich they are attached form a cyclohexane ring.

Method of Forming the Chiral Catalyst

In an illustrative embodiment, the chiral catalyst was prepared bycombining the ruthenium (II) metal, the deprotonated chiral ligand andalkenyl ligand. The deprotonated chiral ligand, formula (III) where M¹and M² are metal ions from Group I or Group II, may be formed bydeprotonating the phenolic groups of the chiral ligand with a suitablebase as shown in Scheme 1.

To promote complexation of the chiral ligand with the ruthenium (II)metal, the chiral ligand was deprotonated with a base, withdeprotonation occurring at both hydroxyl groups to form phenoxideanions. Any suitable base known to one skilled in the art to deprotonatea phenol may be employed to deprotonate the chiral ligand. Suitablebases include metal amines, including for example, lithiumdiisopropylamine (LiN(CH(CH₃))₂; metal alkoxides including for examplepotassium tert-butoxide, sodium ethoxide, sodium methoxide; and metalalkyls, including for example methyl lithium, n-butyl lithium, t-butyllithium, hexyl lithium, octyl lithium, methylmagnesium bromide,methylmagnesium chloride and the like. Preferably the base is lithiumdiisopropylamide (LiN(CH(CH₃)₂)₂). Preferably at least two moleequivalents of base are used as compared to the chiral ligand.

The deprotonation of the chiral ligand may be performed in any suitableinert solvent known to one skilled in the art. Preferably the solvent istetrahydrofuran (THF). The deprotonation is conducted at a suitabletemperature to deprotonate the phenol groups of the chiral ligand.Preferably the deprotonation is conducted at about less than 15° C.,more preferably less than about 10° C., even more preferably betweenabout 0 and about 10° C.

The deprotonated phenoxide groups of the chiral ligand coordinate withthe ruthenium (II) metal to form a complex. Due to the chirality of thechiral ligand, complexation of the deprotonated chiral ligand with theruthenium (II) metal imparts chirality to the ruthenium catalyst. Thechiral nature of the catalyst influences the stereoselectivity of thecyclopropanation reaction.

An alkenyl ligand was also combined with ruthenium (II) metal and thedeprotonated chiral ligand. Without wishing to be bound by theory, thealkenyl ligand is believed to coordinate to the ruthenium (II) metal andoccupy an axial coordination site, forming a catalyst of formula (V) or(VI), depending upon whether one or two alkenyl ligands coordinate.

Strong donor ligands such as pyridyl donating ligands, phosphorusdonating ligands and tertiary amine ligands have been used previouslywith ruthenium (II) catalysts and are thought to occupy an axialcoordination position on the ruthenium (II) metal. Pyridyl donatingligands are pyridine compounds which can act as a ligand, where thenitrogen atom of the pyridine ring acts as the Lewis base and electronpair donor to form a complex with the ruthenium metal. A phosphorusdonating ligand is a ligand containing a phosphorus atom, where thephosphorus atom can act as the Lewis base and electron pair donor toform a complex with the ruthenium metal. A tertiary amine ligand iswhere the nitrogen atom acts as a Lewis base and electron pair donor toform a complex with the ruthenium metal.

Without wishing to be bound by theory, the present invention providesalkenyl ligands which are thought to occupy an axial coordinationposition on the ruthenium (II) metal. Pyridyl donating ligands,phosphorus donating ligands and tertiary amine ligands are preferablynot employed in the catalyst preparation or cyclopropanation reaction.Better stereoselectivity such as enantioselectivity and higher yieldshave been found in the present invention when alkenyl ligands are usedas compared to pyridyl or phosphorus donating ligands.

The combination of the alkenyl ligand, ruthenium (II) metal anddeprotonated chiral ligand forms a catalyst which is active. Although insome cases it may be desirable to isolate the catalyst, preferably thecatalyst is formed in situ, not isolated, and not purified prior to usein the cyclopropanation reaction. Generating the catalyst in situ offersadvantages over using a isolated catalyst such as: (i) convenience; and(ii) minimal handling of a catalyst which may be air or moisturesensitive. Without wishing to be bound by theory, the properties whichmake a catalyst stable enough for isolation, may also decrease thereactivity of the catalyst. Using an in situ catalyst may allow a morereactive catalyst to be used that gives better selectivity, yield andturnover than using an isolated catalyst.

In one embodiment, the formula of the alkenyl ligand is the same as theformula of the alkenyl substrate to be used in the cyclopropanationreaction. This minimizes the generation of impurities. For example, whenthe alkenyl ligand is different than the alkenyl substrate, the alkenylligand can enter into transition metal catalyzed side reactions known toone skilled in the art, and form impurities. When the alkenyl ligand isthe same as the alkenyl substrate, impurities are minimized.

The combining of the ruthenium (II) metal, alkenyl ligand, anddeprotonated chiral ligand may be done in any suitable order. In someaspects it may be desirable to generate the deprotonated chiral ligandin the presence of the ruthenium (II) metal and or alkenyl ligand, forexample, when ruthenium (II) metal and the functional groups on thealkenyl ligand are compatible with the deprotonation conditions. Thedeprotonated chiral ligand is formed by deprotonating the phenol groupsof the chiral ligand with a suitable base as discussed previously.

The catalyst preparation reaction is carried out with various amounts ofmetal, deprotonated chiral ligand and alkenyl ligand. The amount ofdeprotonated chiral ligand used can be greater than the amount ofruthenium (II) metal. Preferably at least one equivalent of thedeprotonated chiral ligand relative to the ruthenium (II) metal is used.The amount of alkenyl ligand is at least twice the amount of theruthenium (II) metal, preferably at least 5 equivalents, more preferablyat least 6 equivalent of the alkenyl ligand relative to the ruthenium(II) metal. In aspects where the alkenyl ligand is the same as thealkenyl substrate, a large excess of alkenyl ligand may be employedrelative to the ruthenium (II) metal.

The combining of the ruthenium (II) metal, deprotonated chiral ligandand alkenyl ligand is preferably done in a suitable solvent, for asuitable length of time, and at a suitable temperature. Suitablesolvents include tetrahydrofuran (THF), and combinations ofTHF/cyclohexane. The ruthenium (II) metal, deprotonated chiral ligandand alkenyl ligand are combined at a suitable temperature. A suitabletemperature for combining the ruthenium (II) metal, deprotonated chiralligand and alkenyl ligand is between about −10° C. and about 30° C.,preferably between about 0° C. and about 25° C., more preferably betweenabout 0° C. and about 5° C. After combining the ruthenium (II) metal,deprotonated chiral ligand and alkenyl ligand, the mixture is stirredfor a suitable amount of time to allow the catalyst to form. The mixtureis stirred for at least 12 h, preferably at least 1 h, more preferablyat least 5 minutes.

Method for Stereoselective Cyclopropanation

In one embodiment of the present invention, a method of stereoselectivecyclopropanation is provided. In the cyclopropanation method, thecatalyst is contacted with a carbene precursor in the presence of analkenyl substrate.

Carbene Precursor

A carbene precursor is a compound used to generate a carbene at thecoordination site of a transition metal, in particular at thecoordination site of ruthenium. Preferably, the carbene precursor is adiazo compound wherein the carbene is generated by the removal of N₂ asnitrogen gas from the solution. Examples of diazo compounds which arecarbene precursors include ethyl diazoacetate, t-butyl diazoacetate,2,3,4-trimethyl-3-pentyl diazoacetate, menthyl diazoacetate,2,5-dimethyl-4-hexen-2-yl diazoacetate, 3-(diazoacetyl)amino propionate,and diazoacetylamino acetate.

In one embodiment, the carbene precursor is a diazoester.

In one embodiment, the carbene precursor is selected from the groupconsisting of ethyl diazoacetate, t-butyl diazoacetate, and menthyldiazoacetate.

In another embodiment, the carbene precursor is ethyl diazoacetate.

In one embodiment, the carbene precursor is of the formula (VII):

where R⁷ is selected from the group consisting of substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₃₋₈ cycloalkyl,C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted or unsubstituted C₃₋₁₀heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted C₅₋₁₀ heteroaryl and substituted or unsubstitutedarylakyl.

In one embodiment, R⁷ is selected from the group consisting ofsubstituted or unsubstituted C₁₋₈alkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino,and substituted or unsubstituted C₆₋₁₀ aryl.

In another embodiment, R⁷ is selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, and C₁₋₁₀ alkoxy.

In one preferred embodiment, R⁷ is C₁₋₁₀ alkoxy.

In another preferred embodiment, R⁷ is selected from the groupconsisting of —OEt, —OtBu, and —O-(menthyl).

Alkenyl Substrate

In the stereoselective cyclopropanation method, the catalyst iscontacted with the carbene precursor in the presence of an alkenylsubstrate. The carbon atoms of the alkenyl substrate form two of thecarbon atoms of the cyclopropyl ring that is formed. Any suitablealkenyl substrate can be used which leads a cyclopropyl product which isenriched in one stereoisomer. Preferably the alkenyl substrate is aterminal alkene of formula (VIII):

where R⁸ is selected from the group consisting of halogen, —CN,—C(O)R^(a), —CO₂R^(a), —C(O)NR^(a)R^(b), —OR^(a), —OC(O)R^(a),—OC(O)NR^(a)R^(b), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)₂NR^(a)R^(b),—NO₂, —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),—NR^(a)S(O)₂R^(b), —NR^(a)C(O)NR^(b)R^(c), substituted or unsubstitutedC₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted 3- to10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, andsubstituted or unsubstituted 5- to 10-membered heteroaryl;

where R^(a), R^(b), and R^(c) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

R^(a) and R^(b), R^(b) and R^(c) or R^(a) and R^(c) may, together withthe atoms to which they are attached, form a substituted orunsubstituted 5-, 6-, or 7-membered ring; and

where R⁹ is selected from the group consisting of hydrogen, and C₁₋₈alkyl.

In one embodiment, the alkenyl substrate is of formula (II):

which is also referred to as 2,3-dihydro-4-vinylbenzofuran and VBF,herein.

In one embodiment, R⁸ is selected from the group consisting of halogen,—CN, —C(O)R^(a), —CO₂R^(a),—C(O)NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a),—S(O)₂NR^(a)R^(b), and —NO₂.

In another embodiment, R⁸ is selected from the group consisting of—OR^(a), —SR^(a), and —NR^(a)R^(b).

In another embodiment, R⁸ is selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl.

In another embodiment, R⁸ is selected from the group consisting ofsubstituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl.

In another embodiment, R⁸ is substituted or unsubstituted 3- to10-membered heterocyclyl.

In one embodiment, R⁹ is hydrogen.

In another embodiment, R⁹ is C₁₋₈ alkyl.

In another embodiment, R⁹ is methyl.

Cyclopropyl Product

In the stereoselective cyclopropanation method, a cyclopropyl product isformed which is enriched in one stereoisomer. Preferably thecyclopropatiion method is enantioselective wherein one enantiomer isformed preferentially as compared to the partner enantiomer. As anillustrative example, when the carbene precursor is of formula (VII) andthe alkenyl substrate is of formula (VIII), a cyclopropyl product offormula (IX) is formed according to the following scheme:

where R⁷, R⁸, and R⁹ are as defined above. The cyclopropyl product isformed in at least 50% yield, preferably at least 80%, more preferablyat least 90% and even more preferably at least 95%.

The cyclopropyl product has a cis or trans configuration, depending onthe relative size and nature of R⁸ and R⁹. When R⁹ is hydrogen,preferably the trans product is formed as shown in the following scheme.

The amount of trans cyclopropyl product formed in comparison to ciscyclopropyl product is determined by dividing the amount of transcyclopropyl product by the sum of the amount of cis and transcyclopropyl products, and multiplying this number by 100. The amount ofcis or trans product can be measured in either moles or mass. Preferablythe trans cyclopropyl product is formed in greater than about 80%, morepreferably greater than about 90% and even more preferably greater thanabout 95%.

Each of the cis and trans isomers can be evaluated for enantiomericexcess. Enantiomeric excess (ee) is equal to 100 times the mole fractionof the major enantiomer minus the mole fraction of the minor enantiomer.The enantiomeric excess is preferably greater than about 80%, morepreferably greater than about 90%.

The stereoselective cyclopropanation reaction is carried out withvarious amounts of catalyst, carbene precursor and alkenyl substrate.The amount of carbene precursor and alkenyl substrate may be the same orone may be used in excess. In this case, the reagent present in thelesser amount is referred to as the limiting reagent. Preferably thealkenyl substrate is the limiting reagent.

An advantage of the present invention is that the cyclopropanationreaction can be carried out with good stereoselectivity and in highyield when the alkenyl substrate is used as the limiting reagent. Thisis particularly important when the alkenyl substrate requires alaborious synthesis or is costly to synthesize or purchase.

Another advantage of the present invention is that the cyclopropanationreaction can be carried out with good stereoselectivity and in highyield without using a large excess of the carbene precursor. Often areaction is driven to completion by using a large excess of thenon-limiting reagent, for example 5-fold, 10-fold or even greater excessof the non-limiting reagent. When the non-limiting reagent is thecarbene precursor, such as a diazo compound, use of an excess of thediazo compound creates an unsafe operating condition, especially onlarge scale such as in a manufacturing plant. The use of excess diazocompound such as diazoesters is undesirable due to: (i) the build-up ofthe diazo compound in the reactor; diazo compounds can be explosive andthe reactor concentration of this reagent must be kept low; (ii) therapid addition of the diazo compound can lead to an exothermic reactionthat can be difficult to control; (iii) for each mole of the diazocompound that is consumed, a mole of nitrogen is released; a rapidincrease in the rate of the reaction in the presence of a highconcentration of the diazo compound could release a bulbous amount ofnitrogen that may not be able to be effectively vented from the reactor,thus leading to a pressure build-up in the reactor and creating anunsafe condition; (iv) the use of a large excess of diazo compoundcreates an unsafe condition, requires the handling, transporting andstorage of excess diazo compound than theoretically required in thereaction which is significant at manufacturing scale, requires extramonitoring to determine the fate of the excess diazo compound used inthe reaction, and is inefficient.

Accordingly, preferably the alkenyl substrate is used as the limitingreagent and less than about 2.0 equivalents of the carbene precursor isused in the stereoselective cyclopropanation reaction. In anotherembodiment, when the alkenyl substrate is the limiting reagent, betweenabout 1.05 and about 2.0 equivalents of the carbene precursor are usedas compared to the limiting reagent, preferably between about 1.1 andabout 1.8, more preferably between about 1.2 and about 1.5 equivalents,even more preferably about 1.3 equivalents.

The metal catalyst is used in amount of at least 0.05 mole % of thelimiting reagent, preferably between about 0.05% to about 10%, morepreferably between about 0.1 to about 5%, even more preferably betweenabout 0.5% and 3%.

The stereoselective cyclopropanation reaction is carried out in asolvent, with organic solvents being preferred. Preferably reactionsolvent is THF or toluene, or a combination thereof. Additional solventssuch as cyclohexane may also be present. A single solvent may be used,or a combination of solvents may be used.

The stereoselective cyclopropanation reaction is preferably carried outat a suitable reaction temperature. Any suitable temperature may bechosen which affords the desired yield and stereoselectivity of thecyclopropyl product. The reaction temperature is usually below or at theboiling point of the solvent. Preferably the reaction temperature isbetween about 0° C. and about 40° C., more preferably between about 20°C. and about 30° C.

The stereoselective cyclopropanation reaction is carried out for asuitable time to afford the desired yield and stereoselectivity of thecyclopropyl product. Alternatively, the reaction can be carried out fora suitable time to consume the limiting reagent. The reaction time is atleast 1 h, preferably between about 1 h and about 10 h, more preferablybetween abut 2 h and about 5 h.

It is important to note that one skilled in the art would realize thatoptimization of the yield and the stereoselectivity can be achieved byaltering the reaction conditions. For example, such optimization caninclude changing the solvent, the temperature of various stages of thereaction, the equivalents the metal catalyst, the equivalents of thecarbene precursor, and the equivalents of the alkenyl substrate.

The following examples are offered to illustrate, but not to limit, theclaimed invention.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA) unless otherwiseindicated. The salen complex was obtained from Strem Chemicals, Inc.¹H-NMR were recorded on an NMR spectrometer. Significant peaks aretabulated in the order: multiplicity (br, broad; s, singlet; d, doublet;t, triplet; q, quartet; m, multiplet) and number of protons. Massspectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Asingle m/e value is reported for the M+H (or, as noted, M−H, or M+Na)ion containing the most common atomic isotopes. Isotope patternscorrespond to the expected formula in all cases.

Example 1 Ru/Salen/Cylcohexene Catalyst

In a 50-mL 3-neck neck round bottom flask fitted with a temperatureprobe, nitrogen inlet, magnetic stir bar and a septum was added(1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene)(salen; 2.17 g, 4 mmol) and 25 mL of anhydrous THF. The resultantsolution was cooled to 0-5° C. Lithium diisopropylamide(tetrahydrofuran)(1.5 M solution in cyclohexane; 5.3 mL, 8 mmol) was added slowly at arate that the reaction temperature was kept below 5° C. The solution wasstirred for 1 hour at 0-5° C.

In a 250-mL round bottom flask was chargeddichloro(p-cymene)ruthenium(II) dimer (1.21 g, 2 mmol), cyclohexene(0.92 g, 11.2 mmol) and anhydrous THF (60 mL). The mixture was stirred.The salen solution was added in one portion to the stirred suspension atambient temperature. The salen reaction flask was rinsed with 10 mL ofTHF and the rinse solution was transferred to the 250-mL flask. Theresultant mixture was stirred overnight. The catalyst solution can beused without further work-up in the cyclopropanation reaction asdescribed below. Alternatively, the solution can be concentrated todryness to provide a green solid that can be used in thecyclopropanation reaction.

Example 2 One Pot Procedure for Ru/Salen/Cylcohexene Catalyst

In a 50-mL round bottom flask fitted with a temperature probe, nitrogeninlet, magnetic stir bar and a septum was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene)(salen, 540 mg, 1 mmol) and 23.5 mL of anhydrous THF. The resultingsolution was cooled to 0-5° C. To this was added LDA (1.5 M incyclohexane, 1.34 mL, 2 mmol) at a rate that allowed the reactiontemperature to be maintained below 5° C. The reaction mixture wasstirred for 0.5 hour at 0-5° C. To this was addeddichloro(p-cymene)ruthenium (II) dimer (300 mg, 0.5 mmol), followed byVBF (0.4 g, 2.8 mmol). After the addition, the mixture was stirred atambient temperature. The catalyst solution can be used without furtherwork-up in the cyclopropanation reaction as described below.Alternatively, the solution can be concentrated to dryness to provide agreen solid that can be used in the cyclopropanation reaction.

Example 3 Ru/Salen/1-hexene Catalyst

The Ru/salen/1-hexene catalyst was prepared according to the procedurefor Ru/salen/cyclohexene except that 1-hexene was used in place ofcyclohexene. The resulting catalyst solution was found to be active inthe cyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran withethyl diazoacetate.

Example 4 Ru/Salen/Ethylene Catalyst

The Ru/salen/ethylene catalyst was prepared according to the procedurefor Ru/salen/cyclohexene except that ethylene was used in place ofcyclohexene. Excess ethylene gas was bubbled through a solution ofdichloro(p-cymene)ruthenium(II) dimer in anhydrous THF, followed byaddition of the deprotonated salen ligand. The resulting catalystsolution was found to be active in the cyclopropanation reaction of4-vinyl-2,3-dihydrobenzofuran with ethyl diazoacetate.

Example 5 Representative Procedure for (1R,2R)-ethyl2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate Prepared Using InSitu Generated Ru/Salen/Ethylene Catalyst

In a 3-neck neck round bottom flask fitted with a temperature probe,nitrogen inlet, magnetic stir bar and a septum was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene)(salen) and anhydrous THF. The resultant solution was cooled to 0-5° C.Lithium diisopropylamide(tetrahydrofuran) (1.5 M solution incyclohexane; 2 equivalents) was added slowly at a rate that the reactiontemperature was kept below 5° C. The solution was stirred for 1 hour at0-5° C.

In a round bottom flask was charged dichloro(p-cymene)ruthenium(II)dimer (0.5 equivalents relative to the salen) and anhydrous THF andethylene gas was bubbled through the solution. The mixture was stirred.The salen solution was added in one portion to the stirred suspension atambient temperature. The salen reaction flask was rinsed with THF andthe rinse solution was transferred to the round bottom flask. Theresultant mixture was stirred overnight.

To a mixture of the in situ generated catalyst prepared in the previousparagraph was charged 4-vinyl-2,3-dihydrobenzofuran and toluene. To thestirred solution was added a solution of EDA in toluene. In someexperiments, a second aliquot of EDA was charged. The solution wasconcentrated to remove the THF from the reaction solution. The remainingsolution was transferred to a 3-neck round bottom flask equipped with amechanical stirrer and temperature probe connected to a J-Kemcontroller. To the solution was added a solution of sodium hydroxidefollowed by tetra-n-butylammonium hydroxide. The mixture was stirred andheated to 60° C. The phases were separated and the organic phase waswashed with water. The combined aqueous extracts were extracted with oftoluene. The aqueous phase was combined with MTBE and cooled to 10° C.The pH of the aqueous phase was adjusted to 2-3 with phosphoric acid.The phases were mixed and then separated. The MTBE phase was washed withwater. The MTBE phase was filtered through Whatman Qualitative #1 filterpaper. The MTBE phase was concentrated to an oil.

TABLE 1 Cyclopropanation of VBF with in situ Ru/salen/ethyene catalystExp. Reaction Temp. Cis Trans VBF Remaining  5 60° C.^(a) 4.3% 83.8%11.8%   6^(b) RT 4.7% 92.8% 2.5%  7 0-5° C. for 6 hours, then 6.4% 94.6%None Detected RT overnight.^(c)  8^(d) RT 5.1% 94.9% None Detected 9^(e) RT 4.8% 92.6% 2.6% 10^(f) RT 4.5% 95.5% None Detected 11^(g) RT4.8% 95.2% None Detected ^(a)Started at RT and heated to 60° C. ^(b)Slowaddition of EDA. Mild exotherm observed. ^(c)The reaction is slow at0-5° C. and after warming to RT the reaction rate increases.^(d)Catalyst solution filtered through silica gel. ^(e)Unfilteredcatalyst solution used in Exp. 8. ^(f)Used 1.2 eq of salen in catalystsynthesis. ^(g)Same catalyst solution as used in exp. 10, except storedunder N₂ at RT for 10 days prior to use.

The experiments in Table 1 used 2.6 equivalents of EDA relative to VBF,and 0.1-0.2 equivalents of catalyst. Experiments 5-6 illustrate thatadding EDA at lower temperatures led to higher consumption of VBF.Experiments 9-10 illustrate that filtering the in situ catalyst solutionled to higher consumption of VBF. Experiment 11 illustrates that freshlyprepared in situ catalyst gives similar results to in situ catalyst thathas been stored for 10 days.

Example 12 Ru/Salen/4-vinyl-2,3-dihydrobenzofuran Catalyst

The Ru/salen/4-vinyl-2,3-dihydrobenzofuran catalyst was preparedaccording to the procedure for Ru/salen/cyclohexene except that4-vinyl-2,3-dihydrobenzofuran was used in place of cyclohexene. Theresulting catalyst solution was found to be active in thecyclopropanation reaction of 4-vinyl-2,3-dihydrobenzofuran with ethyldiazoacetate.

Example 13 (1R,2R)-ethyl2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate Prepared Using InSitu Ru/Salen/4-vinyl-2,3-dihydrobenzofuran Catalyst

One mmol of the Ru/salen/4-vinyl-2,3-dihydrobenzofuran catalyst wasprepared in situ in a total of 50 mL of anhydrous THF as described abovein a 250 mL round bottom flask equipped with a mechanical stirrer, atemperature probe, a Claisen head fitted with a nitrogen inlet and aninlet for the addition of an ethyl diazoacetate (EDA) solution. To thein situ catalyst solution was charged 4-vinyl-2,3-dihydrobenzofuran(14.64 g, 100 mmol) in 15 mL of toluene. To the stirred solution wasslowly added a solution of EDA (20.19 g, 180 mmol) in 90 mL of toluenevia a Masterflex pump. A slight exotherm was noted but was easilycontrolled by the adjustment of the rate of EDA addition. After 3 hours,the VBF was consumed and 32 mL of the EDA solution was remaining. Theremaining EDA solution was not added to the reaction vessel.Approximately 130 mmol of EDA or 1.3 equivalents were required toconsume the VBF. The solution was concentrated to remove the THF fromthe reaction solution. Approximately 40 mL of solvent was removed. Theremaining solution was transferred to a 500-mL 3-neck round bottom flaskequipped with a mechanical stirrer and temperature probe connected to aJ-Kem controller. To the solution was added a solution of sodiumhydroxide (29.54 g 370 mmol, of 50% aqueous sodium hydroxide solutiondiluted with 120 mL of water) followed by tetra-n-butylammoniumhydroxide (16.12 g, 33 mmol). The mixture was stirred and heated to 60°C. for 280 mins. The phases were separated and the organic phase waswashed with 75 mL of water. The combined aqueous extracts were extractedwith 75 mL of toluene. The aqueous phase was combined with 200 mL ofMTBE and cooled to 10° C. The pH of the aqueous phase was adjusted to2-3 with phosphoric acid. The phases were mixed and then separated. TheMTBE phase was washed with 4×50 mL of water. The MTBE phase was filteredthrough Whatman Qualitative #1 filter paper. The MTBE phase wasconcentrated to an oil that solidified upon standing to give 22.13 g(95%) of a mixture of cyclopropyl acid isomers. 97.7:2.3 trans/cis byHPLC area counts; trans isomer (1R,2R) 91.8%: trans enantiomer (1S,2S):8.2% by HPLC area counts; % enantiomeric purity (83.6% ee)

Example 14 Isolated Ru/Salen/Pyridine Catalyst

The isolated Ru/salen/pyridine catalyst was obtained from SonBinh Nguyenprepared according to the method of Miller et al. (Angew. Chem Int. Ed.2002, 41, 2953-2956). According to Miller et al. the Ru/salen/pyridinecatalyst has the structure:

Example 15 (1R,2R)-ethyl2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate Prepared UsingIsolated Ru/Salen/Pyridine Catalyst

To the isolated Ru/salen/pyridine (4 mg, 0.005 mmol) catalyst wascharged 4-vinyl-2,3-dihydrobenzofuran (0.37 g, 2.53 mmol) in 4.44 mL oftoluene. To the stirred solution was slowly added a solution of EDA(0.32 g, 2.80 mmol) in 1.0 mL of toluene over 30 minutes. After 2.5hours, an aliquot was removed, and the sample was analyzed by in-processHPLC. The desired cyclopropane ethyl ester was not formed, and only VBFwas detected. The catalyst was not active in the promotion of thecyclopropanation of VBF.

Example 16 Isolated Ru/Salen/Triphenylphosphine Catalyst

The isolated Ru/salen/triphenylphosphine catalyst was obtained fromSonBinh Nguyen prepared according to the method of Miller et al. (Angew.Chem Int. Ed. 2002, 41, 2953-2956). According to Miller et al. theRu/salen/triphenylphosphine catalyst has the structure:

Experiment 17: (1R,2R)-ethyl2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate Prepared UsingIsolated Ru/Salen/Triphenylphosphine Catalyst

To the isolated Ru/salen/triphenylphosphine (4 mg, 0.005 mmol) catalystwas charged 4-vinyl-2,3-dihydrobenzofuran (0.37 g, 2.53 mmol) in 4.4 mLof toluene. To the stirred solution was slowly added a solution of EDA(0.32 g, 2.80 mmol) in 1.0 mL of toluene over 15 minutes. After 2 hours,an aliquot was removed and analyzed by in-process HPLC. The cyclopropaneethyl ester was formed in just 4% (%AUC) yield, and after 20 hours theyield of the ethyl ester was unchanged.

Examples 15 and 17 illustrate the use of isolated Ru/salen/pyridine andRu/salen/triphenylphosphine in the stereoselective cyclopropanation of4-vinyl-2,3-dihydrobenzofuran. Neither of these isolated catalystsprovided satisfactory results. Specifically, the reaction with theisolated Ru/salen/pyridine catalyst provided none of the desired(1R,2R)-ethyl 2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylateproduct. The reaction with the isolated Ru/salen/triphenylphosphinecatalyst provided only a small amount of the desired (1R,2R)-ethyl2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate product. Withoutwishing to be bound by theory, the isolated Ru/salen/pyridine catalystand isolated Ru/salen/triphenylphosphine catalyst may be unstable. Thecatalysts may degrade over time or due to exposure to air or moisture.Further experiments were conducted by generating the Ru/salen/pyridinecatalyst in situ as detailed below.

Example 18 Representative Procedure for (1R,2R)-ethyl2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate Prepared Using InSitu Generated Ru/Salen/Pyridine Catalyst

In a 3-neck neck round bottom flask fitted with a temperature probe,nitrogen inlet, magnetic stir bar and a septum was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis-(3,5-di-t-butylsalicylidene)(salen) and anhydrous THF. The resultant solution was cooled to 0-5° C.Lithium diisopropylamide(tetrahydrofuran) (1.5 M solution incyclohexane; 2 equivalents) was added slowly at a rate that the reactiontemperature was kept below 5° C. The solution was stirred for 1 hour at0-5° C.

In a round bottom flask was charged dichloro(p-cymene)ruthenium(II)dimer (0.5 equivalents relative to the salen), pyridine (10 equivalentsrelative to the salen) and anhydrous THF. The mixture was stirred. Thesalen solution was added in one portion to the stirred suspension atambient temperature. The salen reaction flask was rinsed with THF andthe rinse solution was transferred to the round bottom flask. Theresultant mixture was stirred overnight.

To a mixture of the in situ generated catalyst prepared in the previousparagraph was charged 4-vinyl-2,3-dihydrobenzofuran and toluene. To thestirred solution was added a solution of EDA in toluene. In someexperiments, a second aliquot of EDA was charged. The solution wasconcentrated to remove the THF from the reaction solution. The residuewas analyzed by in-process HPLC.

TABLE 2 Results of in situ Ru/salen/pyridine catalyst in thecyclopropanation of 4-vinyl-2,3-dihydrobenzofuran % Eq. conversionRu/Salen/ Addition Time of VBF to Exp. pyr Eq. EDA Temp. for EDA CPA¹ 190.04 1.1 60° C. Slow-overnight  21% 20 0.04 2.5 (First) 60° C. Rapidaddition;  50% (First) 2.5 60° C. 2^(nd) addition 100% (Second) over 1hour (Second) 21 0.04 2.5 (First) 60° C. Slow 1 hour  17% (First) 2.560° C. addition;  50% (Second) 2^(nd) rapid addition (Second) over 7 min22 0.04 5 60° C. Rapid addition  97% over 9 minutes ¹CPA = (1R,2R)-ethyl2-(2,3-dihydrobenzofuran-4-yl)cyclopropanecarboxylate

The results in Table 2 illustrate that the Ru/salen/pyridine catalystgenerated in situ is active in the cyclopropanation reaction. Experiment19 illustrates that the slow addition of ethyl diazoacetate (EDA)affords only a 21% yield of the product. Experiment 20 illustrates thatrapid addition of 2.5 equivalents afforded a 50% conversion to product.When an additional 2.5 eq. of EDA was added over 1 h, the reaction wentto 100% completion. Experiment 21 illustrates that the slow addition of2.5 eq. of EDA over 1 h afforded only 17% conversion to product. Evenafter adding an additional 2.5 equivalents of EDA over 7 min. thereaction was still incomplete, with only a 50% conversion to product.

In experiment 22, 97% conversion was obtained using 5 equivalents of EDAwith a rapid addition over 9 minutes. However, the need for a rapidaddition of EDA to the reaction creates an unsafe operating conditionespecially on large scale such as in a pilot plant or manufacturingfacility due to: (i) the build-up of EDA in the reactor; EDA isexplosive and the reactor concentration of this reagent must be keptlow; (ii) the rapid addition of EDA leads to an exothermic reaction thatwould be difficult to control; (iii) for each mole of EDA that isconsumed, a mole of nitrogen is released; a rapid increase in the rateof the reaction in the presence of a high concentration of EDA couldrelease a bulbous amount of nitrogen that may not be able to beeffectively vented from the reactor, thus leading to a pressure build-upin the reactor and creating an unsafe condition; (iv) 5 equivalents ofEDA were necessary to drive the reaction to completion; the use of suchan excess of EDA creates an unsafe condition, requires the handling,transporting and storage of 4 times the amount of EDA than theoreticallyrequired in the reaction which is significant at manufacturing scale,requires extra monitoring to determine the fate of the excess EDA usedin the reaction, and is inefficient. For at least these reasons, analternative cyclopropanation catalyst and method was developed. Inparticular, conditions which gave high yields and stereoselectivitywhich utilized the alkenyl substrate as the limiting reagent andminimized the amount of the carbene precursor were developed.

It is therefore intended that the foregoing detailed description beregarded as illustrative rather than limiting, and that it be understoodthat it is the following claims, including all equivalents, that areintended to define the spirit and scope of this invention.

1. A method of stereoselective cyclopropanation comprising the step of:combining a carbene precursor and an alkenyl substrate in the presenceof a chiral catalyst to form a cyclopropyl product, the chiral catalystis prepared in situ by the step of: combining an alkenyl ligand and adeprotonated chiral ligand in the presence of a ruthenium (II) metal;wherein the alkenyl ligand is of formula (I):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈alkyl,C₆₋₁₀aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ is selectedfrom the group consisting of hydrogen, and C₁₋₈ alkyl; and where R⁵ andR⁶ together with the atoms to which they are attached may form acarbocyclic ring; wherein the deprotonated chiral ligand is of formula(III):

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀ heteroaryl; whereR³ and R⁴ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted C₅₋₁₀ heteroaryl and substituted orunsubstituted arylalkyl; where R³ and R⁴ together with the atoms towhich they are attached may form a ring; and where M¹ and M² are each acounterion independently selected from the group consisting of Group Imetal ions and Group II metal ions.
 2. The method of claim 1, whereinthe deprotonated chiral ligand is formed by deprotonating a chiralligand of formula (III) where M¹ and M² are hydrogen with a baseselected from the group consisting of consisting of metal alkoxides,metal amines, and metal alkyls, wherein the metal is selected from thegroup consisting of Group I or Group II metals.
 3. The method of claim1, wherein the alkenyl ligand is the same as the alkenyl substrate. 4.The method of claim 1, wherein the catalyst is prepared in the absenceof an additive selected from the group consisting of a pyridyl donatingligand, a phosphorus donating ligand and a tertiary amine ligand.
 5. Themethod of claim 3, wherein the carbene precursor is an alkyldiazoacetate.
 6. The method of claim 5, wherein the cyclopropyl productis at least 90% trans.
 7. The method of claim 1, wherein the molaramount of carbene precursor is greater than the molar amount of thealkenyl substrate.
 8. The method of claim 1, wherein the deprotonatedchiral ligand is of the formula:


9. The method of claim 8, wherein the alkenyl ligand is selected fromthe group consisting of ethylene, cyclohexene, 1-hexene and2,3-dihydro-4-vinylbenzofuran.
 10. The method of claim 1, wherein thedeprotonated chiral ligand is:

wherein each of the alkenyl ligand and the alkenyl substrate is

wherein the carbene precursor is ethyl diazoacetate; and whereinruthenium (II) metal is [RuCl₂(p-cymene)]₂.
 11. The method of claim 10,wherein the molar amount of carbene precursor is greater than the molaramount of the alkenyl substrate.
 12. A method of stereoselectivecyclopropanation consisting of the steps of: combining an alkenyl ligandand a deprotonated chiral ligand in the presence of a ruthenium (II)metal to form a chiral catalyst in situ; wherein the alkenyl ligand isof formula (I):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ isselected from the group consisting of hydrogen, and C₁₋₈ alkyl; andwhere R⁵ and R⁶ together with the atoms to which they are attached mayform a carbocyclic ring; wherein the deprotonated chiral ligand is offormula (III):

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀ heteroaryl; whereR³ and R⁴ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted C₅₋₁₀ heteroaryl and substituted orunsubstituted arylalkyl; where R³ and R⁴ together with the atoms towhich they are attached may form a ring; and where M¹ and M² are each acounterion independently selected from the group consisting of Group Imetal ions and Group II metal ions; and combining a carbene precursorand an alkenyl substrate in the presence of the chiral catalyst to forma cyclopropyl product.
 13. In the stereoselective cyclopropanation of acarbene precursor and an alkenyl substrate with a chiral catalyst of theformulae (V) or (VI):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ isselected from the group consisting of hydrogen, and C₁₋₈ alkyl; andwhere R⁵ and R⁶ together with the atoms to which they are attached mayform a carbocyclic ring; where R¹ and R² are each independently selectedfrom the group consisting of hydrogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀heteroaryl; where R³ and R⁴ are each independently selected from thegroup consisting of substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino,substituted or unsubstituted C₃₋₁₀ heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted C₅₋₁₀ heteroaryland substituted or unsubstituted arylalkyl; where R³ and R⁴ togetherwith the atoms to which they are attached may form a ring; and where M¹and M² are each a counterion independently selected from the groupconsisting of Group I metal ions and Group II metal ions; theimprovement comprising generating the chiral catalyst in situ.
 14. Acatalyst for stereoselective reactions prepared by the step of combiningan alkenyl ligand and a deprotonated chiral ligand in the presence of aruthenium (II) metal; wherein the alkenyl ligand is of formula (I):

where R⁵ is selected from the group consisting of hydrogen, C₁₋₈alkyl,C₆₋₁₀ aryl, C₅₋₁₀ heteroaryl, C₃₋₁₀ heterocycle; and where R⁶ isselected from the group consisting of hydrogen, and C₁₋₈ alkyl; andwhere R⁵ and R⁶ together with the atoms to which they are attached mayform a carbocyclic ring; wherein the deprotonated chiral ligand is offormula (III):

where R¹ and R² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₁₀ heterocyclyl, substituted or unsubstituted C₅₋₁₀ heteroaryl; whereR³ and R⁴ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₃₋₈ cycloalkyl, C₁₋₁₀ alkoxy, C₁₋₁₂ alkylamino, substituted orunsubstituted C₃₋₁₀ heterocyclyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted C₅₋₁₀ heteroaryl and substituted orunsubstituted arylalkyl; where R³ and R⁴ together with the atoms towhich they are attached may form a ring; and where M¹ and M² are each acounterion independently selected from the group consisting of Group Imetal ions and Group II metal ions.
 15. The catalyst of claim 14,wherein the combining occurs in the absence of an additive selected fromthe group consisting of a pyridyl donating ligand, a phosphorus donatingligand and a tertiary amine ligand.
 16. The catalyst of claim 14,wherein the alkenyl ligand is selected from the group consisting ofethylene, cyclohexene, 1-hexene and 2,3-dihydro-4-vinylbenzofuran. 17.The catalyst of claim 14, wherein the deprotonated chiral ligand is:

wherein the alkenyl ligand is

wherein the ruthenium (II) metal is [RuCl₂(p-cymene)]₂.